Genetically Engineered Animal Models: Physiological Studies with Gastrin in Transgenic Mice

  • G. J. Dockray
  • G. Bate
  • K. Hormi
  • T. Wang
  • A. Varro
  • R. Dimaline


The role of gastrin as a regulator of acid secretion has been appreciated for almost a century.(13) For many years it has been clear that while gastrin may act directly on parietal cells, it also acts on enterochromaffin-like (ECL) cells to control histamine release which in turn stimulates acid secretion.(33) It is presently thought that this effect is of primary physiological importance in the control of post-prandial acid secretion. In addition, gastrin has long been considered to be a regulator of gastric mucosal proliferation, although it remains controversial as to whether or not proliferating cells in the stomach normally express the gastrin-CCKB receptor, which is the main receptor mediating the effect of COOH-terminally amidated gastrins.


Acid Secretion Parietal Cell Vesicular Monoamine Transporter Plasma Gastrin Paracrine Mediator 
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  1. 1.
    Baldwin, G. S. and A. Shulkes. Gastrin, gastrin receptors and colorectal carcinoma. Gut 42: 581–584, 1998.PubMedCrossRefGoogle Scholar
  2. 2.
    Bate, G. W., A. Varro, R. Dimaline, and G. J. Dockray. Control of preprogastrin messenger RNA translation by gastric acid in the rat. Gastroenterol. 111: 1224–1229, 1996.CrossRefGoogle Scholar
  3. 3.
    Bishop, L., R. Dimaline, C. Blackmore, D. Deavall, G. J. Dockray, and A. Varro. Modulation of the cleavage of the gastrin precursor by phosphorylation. Gastroenterology 115: 1154–1162, 1998.PubMedCrossRefGoogle Scholar
  4. 4.
    Blackmore, C. G., A. Varro, R. Dimaline, L. Bishop, D. V. Gallacher, and G. J. Dockray. Measurement of secretory vesicle pH reveals intravesicular alkalinization by vesicular monoamine transporter type 2 resulting in inhibition of prohormone cleavage. J Physiol 531: 605–617, 2001.PubMedCrossRefGoogle Scholar
  5. 5.
    Bordi, C., B. Annibale, C. Azzoni, M. Marignani, G. Ferraro, G. Antonelli, T. D’Adda, G. D’Ambra, and G. Della-Fave. Endocrine cell growths in atrophic body gastritis, critical evaluation of a histological classification. J.Pathol. 182: 339–346, 1997.PubMedCrossRefGoogle Scholar
  6. 6.
    Dempsey, P. J., J. R. Goldenring, C. J. Soroka, I. M. Modlin, R. W. McClure, C. D. Lind, D. A. Ahlquist, M. R. Pittelkow, D. C. Lee, E. P. Sandgren, D. L. Page, and R. J. J. Coffey. Possible role of transforming growth factor a in the pathogenesis of Menetrier’s disease: Supportive evidence from humans and transgenic mice. Gastroenterology 103: 1950–1963, 1992.PubMedGoogle Scholar
  7. 7.
    Desmond, H., S. Pauwels, A. Varro, H. Gregory, J. Young, and G. J. Dockray. Isolation and characterization of the intact gastrin precursor from a gastrinoma. FEBS Lett. 210: 185–188, 1987.PubMedCrossRefGoogle Scholar
  8. 8.
    Dimaline, R., D. Evans, E. R. Forster, A. K. Sandvik, and G. J. Dockray. Control of gastric corpus chromogranin A messenger RNA abundance in the rat. Am.J.Physiol. 264: G583–G588, 1993.PubMedGoogle Scholar
  9. 9.
    Dimaline, R. and A. K. Sandvik. Histidine decarboxylase gene expression in rat fundus is regulated by gastrin. FEBS Lett. 281: 20–22, 1991.PubMedCrossRefGoogle Scholar
  10. 10.
    Dimaline, R. and J. Struthers. Expression and regulation of a vesicular monoamine transporter (VMAT2) in rat stomach: a putative histamine transporter. J.Physiol. 490: 249–256, 1996.PubMedGoogle Scholar
  11. 11.
    Dockray, G. J. Topical review. Gastrin and gastric epithelial physiology. J Physiol (Lond) 518: 315–324, 1999.PubMedCrossRefGoogle Scholar
  12. 12.
    Dockray, G. J., Varro, A., Dimaline, R., and Wang, T. C. The gastrins: their production and biological activities. Ann.Rev.Physiol. 63, 119–139. 2001. Ref Type: GenericCrossRefGoogle Scholar
  13. 13.
    Edkins, J. S. On the chemical mechanism of gastric secretion. Proc.Roy.Soc.Ser.B 76: 376–376, 1905.CrossRefGoogle Scholar
  14. 14.
    Fukui, H., Y. Kinoshita, T. Maekawa, A. Okada, S. Waki, M. D. S. Hassan, H. Okamoto, and T. Chiba. Regenerating gene protein may mediate gastric mucosal proliferation induced by hypergastrinemia in rats. Gastroenterology 115: 1483–1493, 1998.PubMedCrossRefGoogle Scholar
  15. 15.
    Higham, A. D., L. A. Bishop, R. Dimaline, C. G. Blackmore, A. C. Dobbins, A. Varro, D. G. Thompson, and G. J. Dockray. Mutations of RegIalpha are associated with enterochromaffin-like cell tumor development in patients with hypergastrinemia. Gastroenterology 116: 1310–1318, 1999.PubMedCrossRefGoogle Scholar
  16. 16.
    Hocker, M., R. Raychowdhury, T. Plath, H. Wu, D. T. O’Connor, B. Wiedenmann, S. Rosewicz, and T. C. Wang. Sp 1 and CREB mediate gastrin-dependent regulation of chromogranin A promoter activity in gastric carcinoma cells. J.Biol.Chem. 273: 34000–34007, 1998.PubMedCrossRefGoogle Scholar
  17. 17.
    Huebner, V. D., R. Jiang, T. D. Lee, K. Legesse, J. H. Walsh, J. E. Shively, P. Chew, T. Azuma, and J. R. Reeve. Purification and structural characterization of progastrin-derived peptides from a human gastrinoma. J.Biol.Chem. 266: 12223–12227, 1991.PubMedGoogle Scholar
  18. 18.
    Hussain, I., G. W. Bate, J. Henry, P. K. Djali, R. Dimaline, G. J. Dockray, and A. Varro. Identification of vesicular monoamine transporter type 1 (VMAT1) in G-cells and its role in modulating cleavage of G34. J.Physiol. 517: 495–505, 1999.PubMedCrossRefGoogle Scholar
  19. 19.
    Kobayashi, S., T. Akiyama, K. Nata, M. Abe, M. Tajima, N. J. Shervani, M. Unno, S. Matsuno, H. Sasaki, S. Takasawa, and H. Okamoto. Identification of a receptor for Reg (regenerating gene) protein, a pancreatic beta-cell regeneration factor. J Biol.Chem. 275: 10723–10726, 2000.PubMedCrossRefGoogle Scholar
  20. 20.
    Koh, T. J., G. J. Dockray, A. Varro, R. J. Cahill, C. A. Dangler, J. G. Fox, and T. C. Wang. Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation. J.Clin.Invest. 103: 1119–1126, 1999.PubMedCrossRefGoogle Scholar
  21. 21.
    Konda, Y., H. Kamimura, H. Yokota, N. Hayashi, K. Sugano, and T. Takeuchi. Gastrin stimulates the growth of gastric pit with less-differentiated features. Am.J Physiol 277: G773–G784, 1999.PubMedGoogle Scholar
  22. 22.
    Lefebvre, O., M. P. Chenard, R. Masson, J. Linares, A. Dierich, M. LeMeur, C. Wendling, C. Tomasetto, P. Chambon, and M. C. Rio. Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. Science 274: 259–262, 1996.PubMedCrossRefGoogle Scholar
  23. 23.
    Macro, J. A., G. W. Bate, A. Varro, C. Vaillant, N. G. Seidah, R. Dimaline, and G. J. Dockray. Regulation by gastric acid of the processing of progastrin- derived peptides in rat antral mucosa. J.Physiol. 502: 409–419, 1997.PubMedCrossRefGoogle Scholar
  24. 24.
    Nemeth, J., B. Taylor, S. Pauwels, A. Varro, and G. J. Dockray. Identification of progastrin derived peptides in colorectal carcinoma extracts. Gut 34: 90–95, 1993.PubMedCrossRefGoogle Scholar
  25. 25.
    Scarff, K. L., L. M. Judd, B. H. Toh, P. A. Gleeson, and I. R. Van Driel. Gastric H(+),K(+)-adenosine triphosphatase beta subunit is required for normal function, development, and membrane structure of mouse parietal cells. Gastroenterology 117: 605–618, 1999.PubMedCrossRefGoogle Scholar
  26. 26.
    Schultheis, P. J., L. L. Clarke, P. Meneton, M. Harline, G. P. Boivin, G. Stemmermann, J. J. Duffy, T. Doetschman, M. L. Miller, and G. E. Shull. Targeted disruption of the murine Na+/H+ Exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. J.Clin.Invest. 101: 1243–1253, 1998.PubMedCrossRefGoogle Scholar
  27. 27.
    Seva, C., C. J. Dickinson, and T. Yamada. Growth-promoting effects of glycine-extended progastrin. Science 265: 410–412, 1994.PubMedCrossRefGoogle Scholar
  28. 28.
    Singh, P., A. Owlia, A. Varro, B. Dai, S. Rajaraman, and T. Wood. Gastrin gene expression is required for the proliferation and tumorigenicity of human colon cancer cells. Cancer Research 56: 4111–4115, 1996.PubMedGoogle Scholar
  29. 29.
    Singh, P., M. Velasco, R. Given, M. Wargovich, A. Varro, and T. C. Wang. Mice overexpressing progastrin are predisposed for developing aberrant colonic crypt foci in response to AOM. Am.J Physiol Gastrointest.Liver Physiol 278: G390–G399, 2000.PubMedGoogle Scholar
  30. 30.
    Varro, A., G. J. Dockray, G. W. Bate, C. Vaillant, A. Higham, E. Armitage, and D. G. Thompson. Gastrin biosynthesis in the antrum of patients with pernicious anemia. Gastroenterology 112: 733–741, 1997.PubMedCrossRefGoogle Scholar
  31. 31.
    Varro, A., J. Henry, C. Vaillant, and G. J. Dockray. Discrimination between temperature- and brefeldin A-sensitive steps in the sulfation, phosphorylation, and cleavage of progastrin and its derivatives. J.Biol.Chem. 269: 20764–20770, 1994.PubMedGoogle Scholar
  32. 32.
    Varro, A., S. Voronina, and G. J. Dockray. Pathways of processing of the gastrin precursor in rat antral mucosa. J.Clin.Invest. 95: 1642–1649, 1995.PubMedCrossRefGoogle Scholar
  33. 33.
    Walsh, J. H. Gastrin. In Walsh, J. H. and G. J. Dockray, eds. Gut Peptides. New York, Raven Press. 1994, 75–121.Google Scholar
  34. 34.
    Walsh, J. H., J. I. Isenberg, J. Ansfield, and V. Maxwell. Clearance and acid-stimulating action of human big and little gastrins in duodenal ulcer subjects. J.Clin.Invest. 57: 1125–1131, 1976.PubMedCrossRefGoogle Scholar
  35. 35.
    Wang, T. C., C. A. Dangler, D. Chen, J. R. Goldenring, T. J. Koh, R. Raychowdhury, R. J. Coffey, S. Ito, A. Varro, G. J. Dockray, and J. G. Fox. Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 118: 36–47, 2000.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang, T. C. and G. J. Dockray. Lessons from genetically engineered animal models. I. Physiological studies with gastrin in transgenic mice. Am.J Physiol 277: G6–11, 1999.PubMedGoogle Scholar
  37. 37.
    Wang, T. C., T. J. Koh, A. Varro, R. J. Cahill, C. A. Dangler, J. G. Fox, and G. J. Dockray. Processing and proliferative effects of human progastrin in transgenic mice. J.Clin.Invest. 98: 1918–1929, 1996.PubMedCrossRefGoogle Scholar
  38. 38.
    Watson, F., R. S. Kiernan, D. G. Deavall, A. Varro, and R. Dimaline. Transcriptional activation of the rat vesicular monoamine transporter 2 promoter in gastric epithelial cells: Regulation by gastrin. J Biol.Chem. 276: 7661–7671, 2001.PubMedCrossRefGoogle Scholar
  39. 39.
    Watson, S. A., D. Michaeli, S. Grimes, T. M. Morris, G. Robinson, A. Varro, T. A. Justin, and J. D. Hardcastle. Gastrimmune raises antibodies that neutralize amidated and glycine-exended gastrin-17 and inhibit the growth of colon cancer. Cancer Research 56: 880–885, 1996.PubMedGoogle Scholar
  40. 40.
    Wu, S. V., A. Giraud, M. Mogard, K. Sunii, and J. H. Walsh. Effects of inhibition of gastric secretion on antral gastrin and somatostatin gene expression in rats. Am.J.Physiol. 258: G788–G793, 1990.PubMedGoogle Scholar
  41. 41.
    Zhang, Z., M. Hocker, T. J. Koh, and T. C. Wang. The human histidine decarboxylase promoter is regulated by gastrin and phorbol 12-myristate 13-acetate through a downstream cis-acting element. J.Biol.Chem. 271: 14188–14197, 1996.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • G. J. Dockray
    • 2
  • G. Bate
    • 1
  • K. Hormi
    • 1
  • T. Wang
    • 2
  • A. Varro
    • 1
  • R. Dimaline
    • 2
  1. 1.Physiological LaboratoryUniversity of LiverpoolLiverpoolUK
  2. 2.Division of GastroenterologyUMass Medical CenterWorcesterUSA

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